A point mutation in the pleckstrin homology domain of the mouse Bruton's tyrosine kinase (btk) gene results in an X-linked immune defect, Xid, characterized by immunological unresponsiveness to polymeric carbohydrate antigens. In Xid mice, B cells specific for phosphocholine (PC) do not develop in peripheral lymphoid tissues because they either fail to be positively selected from the marrow or they are clonally deleted via an antigen-driven, receptor-mediated process. Over-expression of the bcl-2 gene allows PC-specific B cells to survive and mature in Xid mu kappa anti-PC transgenic mice, but PC-specific B cells are not rescued by bcl-2 in Xid mu-only transgenic mice. The failure of bcl-2 to rescue PC-specific B cells in _-only transgenic mice suggests that either it does not correct the btk defect in the antigen-driven selection process that occurs in pre-B and/or in very immature B cells or that a btk-dependent proliferative phase is required for the selection and amplification of the PC-specific B cells in mu-only transgenic mice. The rescue of PC-specific B cells in mu only transgenic mice indicates that bcl-2 can alter receptor-mediated B-cell selection at late stages in B-cell development. The rescued PC-specific B cells in Xid male mice do not exhibit an altered proliferation profile in response to B cell stimulating agents compared to B cells from unmanipulated Xid mice; thus, they fail to respond to soluble anti-mu or PC-Dextran, but they proliferate in response to PC, anti-mu or anti-id conjugated to Sepharose.